1. Field of the Invention
This invention relates to apparatus for use in non-invasive in vivo monitoring of physiological substances such as blood and the like.
2. Discussion of the Art
One particular, but not exclusive, application of the present invention is in the monitoring of blood glucose, for example in the management of diabetes mellitus. It is accepted that the management of diabetes can be much improved by routine monitoring of blood glucose concentration and clinicians suggest that monitoring as often as four times per day is desirable.
The monitoring technique currently available for use by patients involves using a spring loaded lancet to stab the finger to obtain a blood sample which is transferred to a glucose test strip. The concentration is derived either by reading the test strip with a reflectance meter or by visual comparison of colour change against a colour scale. Many diabetics find the testing onerous as the technique is painful, inconvenient, messy, potentially embarrassing and offers a site for the transmittance and acceptance of infection.
Techniques have also been developed for non invasive measurement using transmittance or reflectance spectroscopy. However the required instruments are expensive and it is difficult to obtain accurate and repeatable measurements.
There are also known various types of in vivo chemical sensors. These rely on implanting minimally invasive sensors under the skin surface, but such sensors have poor long term reproducibility and bio-compatibility problems.
There is therefore a need for improved means for routine monitoring of blood glucose in a manner which is simple and straightforward to use.
The present invention makes use of photoacoustic techniques. The fundamentals of photoacoustic techniques are well known per se. A pulse of light, typically laser light, is applied to a substance containing an analyte of interest in solution or dispersion, the wavelength of the applied light being chosen to interact with the analyte. Absorption of the light energy by the analyte gives rise to microscopic localised heating which generates an acoustic wave which can be detected by an acoustic sensor. These techniques have been used to measure physiological parameters in vitro.
U.S. Pat. Nos. 5,348,002 and 5,348,003 (Caro) propose the use of photoacoustics in combination with photoabsorption for the measurement of blood components in vivo. However, the arrangement proposed by Caro has not been demonstrated as a workable system and may suffer from interference to a degree which would preclude useful acoustic signals, and since they would also suffer from interference and resonance effects from hard structures such as bone.
It has also been proposed by Poulet and Chambron in Medical and Biological Engineering and Computing, Nov. 1985, Page 585 to use a photoacoustic spectrometer in a cell arrangement to measure characteristics of cutaneous tissue, but the apparatus described would not be suitable for measuring blood analytes.
Published European Patent Application 0282234A1 (Dowling) proposes the use of photoacoustic spectroscopy for the measurement of blood analytes such as blood glucose. This disclosure however does not show or suggest any means which would permit the required degree of coupling to body tissues for use in vivo.
Accordingly, the present invention provides a sensor head for use in photoacoustic in vivo measurement, comprising a housing shaped to engage a selected body part, light transmission means terminating in said housing so as to transmit light energy form a light source to enter the body part along a beam axis, and acoustic transducer means mounted in the housing to receive acoustic waves generated by photoacoustic interaction within the body part, the acoustic transducer means being disposed in the housing to receive said acoustic wave in a direction of high acoustic energy.
The expression xe2x80x9cdirection of high acoustic energyxe2x80x9d is used herein to denote a direction other than the forward direction of the light beam. Preferably, the transducer means is disposed so as to intercept acoustic energy propagating at right angles to the optical beam axis, or at an angle to the optical beam axis which may be down to about 20xc2x0, typically about 45xc2x0.
An exact measure of the angle of high acoustic energy can be worked out but is dependent upon the specific geometry of the light source, the properties of the tissue and the absorption coefficient of the tissue. One model for understanding the propagation of the acoustic energy in any homogenous media was developed by Huyghens and is called the principle of superposition. In this model each volume element that is illuminated by the light generates an acoustic pressure wave that radiates outward in a spherical manor. The magnitude of the pressure wave at each volume element depends on the intensity of the optical beam at that location, the absorption coefficient of the material at that location, the wavelength of light and on several other physical properties of the material such as the speed of sound and the specific heat. The signal measured at the detector is just the superposition of all pressure waves from all points that are illuminated by the source light. An analytical solution for the pressure wave has been worked out for a few cases in aqueous material. The analytical case that best matches the in-vivo measurements is that of a cylindrical optical beam propagating in a weekly absorbing material. In this case the direction of highest acoustic energy is perpendicular to the optical axis. The base detector location is with the plane of the detector perpendicular to the acoustic energy, or parallel to the optical axis. This is because the acoustic detector has the highest sensitivity when the acoustic energy strikes the detector perpendicular to the plane of the detector. This analytical model is not completely accurate for the in-vivo measurement case because of scattering of the tissue and because the tissue absorbs more than the model predicts. These differences indicate that a different position for the detector will be optimal. A detailed numeric model is required to determine the best detector location and is dependent upon the beam properties (focused to a point, colligated, etc.), body site (finger, earlobe, arm etc.) and wavelength. One skilled in the art can readily develop an appropriate mode. However, suitable locations for a detector will generally be at an angle to the optical axis. Angles between 40 and 90 degrees should be suitable.
In one preferred arrangement, the acoustic transducer means is arranged parallel to the optical beam axis. This arrangement is particularly suitable for use where the selected body part is the distal portion of a finger, in which case the housing may include a generally half-cylindrical depression in which the finger may be placed with the light transmission means aimed at the end of the finger.
Preferably, the acoustic transducer means comprises a piezoelectric transducer which most preferably is of a semi-cylindrical shape. This transducer may be provided with a backing of lead or other dense material, and the backing may have a rear surface shaped to minimise internal acoustic reflection.
Alternative transducer means include a capacitor-type detector, which is preferably small and disk-shaped; an integrated semiconductor pressure sensor; and an optical pressure sensor, for example based on an optical fibre.
In an alternative arrangement, the plane of the transducer may be arranged to be perpendicular to the optical axis to detect the acoustic wave which is propagating in a direction opposite to the direction of the light beam. For example, the acoustic transducer means may be part-spherical with an aperture to allow access for the light beam. This may be particularly suitable for engagement with a body part other than the finger, for example the back of the arm.
The generation of a surface acoustic wave is an inherent aspect of the in vivo pulsed photoacoustic generation in tissue and may be used to characterize tissue properties such as density. A surface wave detector may be provided in the sensing head assembly.
Preferably means are provided for ensuring a consistent contact pressure between the selected body part and the acoustic transducer means. In the case where the selected part is the distal portion of the finger, said means may be provided by mounting the portion of the housing engaged by the finger in a resiliently biased fashion against the remainder of the housing, and providing means to ensure that measurement is effected when the predetermined force or pressure is applied by the subject against the resilient bias. In the case where the selected part is the earlobe, said means may be provided by placing the ear between two plates and applying pressure to the ear with springs or weights or other force method. The two plates holding the ear may contain a removable insert. The two plates may be flat or may be of another shape to optimally position the detector with respect to the beam axis.
In addition, the present invention provides a sensor head for use in photoacoustic in-vivo measurements, comprising a housing shaped to receive a removable insert, a removable insert that engages a selected body part, the insert being fitted to an individual, allowing for a range of sizes of body parts to be used, and further comprising light transmission means terminating in or near said removable insert so as,to transmit light energy from a light source or sources to enter the body part along a beam axis, and an acoustic transducer means mounted in the housing or in the removable insert to receive acoustic waves generated by photoacoustic interaction within the body part to receive said acoustic waves in a direction of high acoustic energy.
From another aspect the present invention provides an in vivo measuring system comprising a sensor head as hereinbefore defined in combination with a light source coupled with the light transmission means, and signal processing means connected to receive the output of the acoustic transducer means and to derive therefrom a measurement of a selected physiological parameter.
Preferably, the light transmission means is a fiber distribution system where each light source is connected to an individual fiber and when multiple light sources are used the multiple fibres are joined by some standard fiber combining method, such as a wavelength division multiplexer or a fiber coupler. The fiber that comes from the light source, or contains the combined light for a multiple source system, is then terminated in proximity to the body part being measured. The fiber could be in contact with the body part or alternatively standard optics, such as lenses, beamsplitters and such, could be employed to convey the light from the end of the fiber to the body part. A reference detector or several reference detectors and beamsplitters can be added to the optical distribution system to determine the energy of the light entering the body part.
Alternatively, the optical distribution system may contain mechanical holders, lenses and such to convey the light from the source, or sources, to a location in proximity to the body part being measured. A reference detector or several reference detectors and beamsplitters can be added to the optical distribution system to determine the energy of the light entering the body part.
The acoustic signal from the detector contains information in both time and frequency, and there may be information from several sources. The processing means is preferably a multi-dimensional processing method, such as Classical Least Squares (CLS) or Partial Least Squares (PLS). Alternatively the processing method may be more flexible, such as a Neural Network. In addition to these methods the signals may be analysed for their frequency content using such techniques as Fourier Analysis or Frequency Filtering In addition techniques may be employed that use time information such as the time delay from source trigger. Techniques that combine both frequency and time information may be employed, such as Wavelet analysis.
The light source is preferably a laser light source and is most suitably a pulsed diode laser, but may utilise a set of such lasers or utilise a tunable laser source. In a particularly preferred form, suitable for use in measuring blood glucose concentration, a laser diode is used with a wave length in the range of approximately 600 nm to 10,000 nm and a pulse duration of the order of 5 to 500 ns.
The delivery to the measurement site may be either directly or by optical fibre with a suitable optical element to focus the beam into the tissue.
Preferably means are provided for time multiplexing multiple sources when multiple sources are used. Each source is switched on, and it generates an optical pulse, or a set of optical pulses. This pulse, or set of pulses, generates an acoustic signal that is detected by the detector. Each source is pulsed in sequence until all sources have been used to generate their own signal.
The measuring system may conveniently be in the form of a self contained system including a power supply and a readout, which may be carried on the person and used at any convenient time.
It is also possible for such a self contained system to incorporate, or to be provided with facilities for connection to, a cellular telephone, two-way pager or other communication device for routine transmission of measurements taken to a central data collection point.
In addition the measuring system may have provision for manipulating the body part under measurement and for performing additional measurement of the tissue to get other information about the state of the physiology of the issue. It is well-known in the art that squeezing a section of tissue to increase the pressure and then releasing the pressure will cause changes in the total blood volume in the measurement site. The present invention may allow for this type of manipulation including the squeezing of a body part, such as an earlobe, and making photo acoustic measurements at several different pressures. The present invention may also allow for the measurement of the temperature of the body site and to apply a correction to the measurements based upon the temperature of the body site.
Another type of physiological manipulation is body temperature. It is known in the art that several parameters involved in the detection of the photo acoustic signal, such as the speed of sound, are dependent upon the temperature of the medium the signal is propagating through (the tissue). Also the profusion of the blood in the small capillaries is dependent upon the temperature of the tissue. Additional information about the tissue can be obtained if the photo acoustic measurement is made at several temperatures, both higher and lower than ambient temperature. This additional information is used to better eliminate interferences to the determination of the analyte under investigation. These are only two examples of manipulating the body site and are not intended to be an exhaustive list, and they can be used in combination with other manipulation techniques.
The in-vivo measuring system may comprise a means for storing calibration coefficients or operation parameters or both calibration coefficients and operational parameters, in order to calibrate the instrument and to set critical operational parameters.
Another aspect of the present invention provides a means for adjusting the calibration coefficients and operational parameters to be specific to a particular person and may be used to adjust for such things as body part size, skin color, skin condition, amount of body fat, efficiency of the detector and efficiency of the source(s).
In addition the present invention may provide for having the specific calibration coefficients and operational parameters be contained in a storage site located in the removable insert. This allows for the system to be both mechanically and operationally configured to a particular individual. Additionally the invention may allow for the calibration coefficients and operational parameters to be stored in two locations, one in the non-removable housing and one in the removable insert with some of the coefficients and parameters stored in each location. This allows for reader system coefficients to be stored in the reader and coefficients specific to an individual to be stored in the removable insert for that person, enabling many people to use the same reader.
Another aspect of the present invention provides means for connecting the non-invasive measuring system to an invasive measuring system for the purpose of calibrating or adjusting the operational parameters of the non-invasive measuring system. Such connection may be accomplished, but is not limited to, communication by a wire, IR link or radio waves.
Another aspect of the present invention provides a method for removing instrument drift from the measurement comprising the steps of:
1. Placing a standard in the reader in place of the body part.
2. Measuring the signal from the standard for each wavelength and storing the values in the calibration storage location.
3. Before making a measurement of a body part, placing the calibration standard in the reader.
4. Measuring the signal from the standard for each source.
5. Comparing the just measured standard values to the stored calibration values.
6. Calculating correction factors for each source wavelength.
7. Removing the standard and placing the body part in the reader.
8. Measuring the signal from the body part for each source.
9. Adjusting the measured values using the calculated correction factors.
In addition to the signal correction factors a correction factor can be calculated for the instrument temperature. This can be applied to each signal with a different correction coefficient.
The invention further provides a method of measuring a biological parameter in a subject, the method comprising the steps of:
directing one or more pulses of optical energy from the exterior into the tissue of a subject along a beam axis, the optical energy having a wavelength selected to be absorbed by tissue
components of interest, thereby to produce a photoacoustic interaction;
detecting acoustic energy resulting from said photoacoustic reaction by means of a transducer positioned to intercept acoustic energy propagating in a direction other than the forward direction of said beam axis; and
deriving from said detected acoustic energy a measure of the parameter of interest; and a corresponding apparatus.